Ion exchange resin treated to control swelling

ABSTRACT

The present invention provides a method and composition for loading one or more drugs in a solution onto one or more ion exchange resin particles to form a drug-loaded resin particle. The drug-loaded resin particle is separated from the solution and dried before recombining the drug-loaded resin particle with the solution to load more drugs onto the drug-loaded resin particle from the solution.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.11/674,921, filed Feb. 14, 2007, which is a continuation in part of U.S.patent application Ser. No. 11/225,834, filed Sep. 13, 2005. Thecontents of the foregoing are incorporated by reference herein in theirentirety.

TECHNICAL FIELD OF THE INVENTION

The present invention relates general to the controlled release ofactive agents, and in particular, to enhance the efficiency in preparingion exchange resins and pharmacologically active drugs adsorbed to ionexchange resin.

BACKGROUND OF THE INVENTION

Without limiting the scope of the invention, its background is describedin connection with ion exchange resins, as an example. Currently, ionexchange resins used in pharmaceutical applications serve a variety offunctions, e.g., providing sustained release, masking tastes,eliminating polymorphism, improving the dissolution of poorly solubledrugs, eliminating deliquescence, reducing water uptake, improvingstability, reducing abuse liability and improving physicalcharacteristics of pharmacologically active drugs. For example, ionexchange resins are used to prolong the continuous release ofpharmacologically active drugs by absorbing the drug to the ionicexchange resin to form a drug-resin complex in which the drug isreleased over time. In certain instances, a rate controlling coating isapplied to the drug-resin complex.

The sustained release drug-resin complex provides a controlled releaseof the pharmacologically active drug over a given period of time. Thus,these complexes allow a continuous or intermittent supply of the activedrug to a subject. The sustained-release drug-resin complex provides aconvenient dosage form that provides a therapeutic drug levelsthroughout an extended period. The release of the drug maintains atherapeutically effective plasma level significantly longer than thatgiven by a typical drug dosage form.

In a general sense, an ion exchange resin can be described as anassembly of polymers that contain ionizable groups distributed along thepolymer backbone. The ionizable groups of the polymer backbone areassociated with ions. When the polymer is combined with a solution ofcounter ions, the counter ions in the solution exchange with the ions ofthe polymer and the counter ions are physically removed from thesolution. Therefore, counter ions (e.g., drug ion) in solution canexchange with the ions of the ion exchange resin (e.g., polymer) throughan ionic interaction, as opposed to a covalent interaction. Thepharmacologically active drug ions can then be eluted from the ionexchange resin to treat the subject.

A substantial portion of the active drug is ionically bound within thepolymer matrix of the ion exchange resin. The active drug elutes fromthe polymer matrix over time to provide a specific release profile. Thesize of the adsorbed drug molecule and/or the size of the polymer resinparticle (e.g., the cross linkage of the cationic exchange resin) may bealtered to control the elution rate. The process of adsorption of apharmacologically active drug to ion exchange resin is a well-knowntechnique to the skilled artisan and the subject of many United Statesand foreign patents. Generally, adsorption is accomplished by mixing apharmacologically active drug and an ion exchange resin in an aqueoussolution, filtering, washing, drying and optionally coating thedrug-resin complex with a water-permeable diffusion barrier.

For example, U.S. Pat. No. 4,996,047 discloses oral pharmaceuticalpreparations, which include a pharmacologically active drug bound to anion-exchange resin to provide a drug-resin complex having a drug contentabove a specified value. The drug-resin complex is subsequently coatedwith a water-permeable diffusion barrier coating that is insoluble ingastrointestinal fluids. Thus, the release of drug is controlled underconditions encountered in the gastrointestinal tract.

One of the major disadvantages with the use of an ion exchange resin asa pharmaceutical delivery agent is that ion exchange resin particles aresusceptible to swelling. For example, ion exchange resins drug complexescan undergo significant swelling when the dry, non-hydrated drug complexcontacts fluids, e.g., water, biological fluids, gastrointestinalfluids. The swelling of the ion exchange resin often ruptures thediffusion barrier coating, which causes a loss of control of thediffusion rate of the drug and alters the drug release profile.

U.S. Pat. No. 4,847,077 discloses sulfonic and cationic exchange resinstreated with a critical amount of glycerin to enhance their coatability.The specification discloses methods to achieve prolonged continuousrelease of a pharmacologically active monobasic drug absorbed on asulfonic acid cationic exchange resin treated with a critical amount ofglycerin. Specifically, controlled release pharmaceutical preparationscontaining coated sulfonic acid cationic exchange resin drug complexparticles are taught, that are treated prior to coating with about 15 to25% by weight of glycerin.

Finally, U.S. Pat. No. 4,221,778 (the '778 patent) teaches apharmaceutical preparation containing a diffusion barrier coated ionexchange resin drug complex treated with a solvating agent. Thesolvating agent retards the rate of swelling in water but does notreduce the overall amount of swelling, only the rate at which swellingoccurs. The '778 patent claims a pharmaceutical preparation having ionexchange resin particles with a pharmacologically active drug absorbedthereon to form drug-resin complex particles. The resin particles havebeen treated with an impregnating agent (e.g., polyethylene glycol,propylene glycol, mannitol, lactose and methylcellulose) in an amountsufficient to retard the rate of swelling in water and subsequentlycoated with a water-permeable diffusion barrier.

SUMMARY OF THE INVENTION

The present inventors recognized a need for a pharmacologically activedrug-resin complex that does not swell or alter the release rate whencontacted with fluids, while reducing the concentration of swellingagent used in the formulations and increasing the compatibility of theswelling reducing agent with pharmacologically active drugs.

The foregoing problems have been recognized for many years and whilenumerous solutions have been proposed, none of them adequately addressall of the problems in a single composition, e.g., controlling theswelling, reducing the concentration of swelling agent, increasing theeffectiveness of the swelling controlling agent and increasing thecompatibility of the swelling reducing agent with pharmacologicallyactive drugs.

The present invention provides a pharmaceutical composition made by theprocess of loading one or more drugs in a solution onto one or more ionexchange resin particles to form drug-loaded resin particles. Thedrug-loaded resin particles are separated from the solution and dried.The drug-loaded resin particles are recombined with the drug solutionand more of the drug is loaded onto the drug-loaded resin particles.

The present invention provides a method of making a pharmaceuticalcomposition by loading, in a solution, one or more substances onto oneor more cationic exchange resin particles to form a loaded resinparticle. One or more sugar alcohols (e.g., between about 0.01% to about10% by weight) are added to the solution to make prior to separating theloaded resin particle from the solution. The loaded resin particle isdried and recombined with the solution to load more drugs onto thedrug-loaded resin particle.

In addition, the present invention provides a method of making adrug-resin compound by loading one or more drugs onto one or more ionexchange resin particles in a solution to form a drug-loaded resinparticles. The drug-loaded resin particles are separated from thesolution and dried. The drugs solution is recombined with thedrug-loaded resin particles to add more drugs to the drug-loaded resinparticles. The drug-loaded resin particles are then dried.

The present inventors have recognized that the nature of the materialused as pharmaceutically acceptable ion exchange resins result in theresin undergoing significant swelling (e.g., up to about a 60% increasein volume) when the non-hydrated resin-drug complex is placed in contactwith fluids, e.g., water, biological fluid, gastrointestinal fluids.When an ion exchange resin-drug complex is coated with a water-permeablediffusion barrier, the swelling of the ion exchange resin often rupturesthe diffusion barrier coating. The damage to the water-permeablediffusion barrier coating results in a loss of control of the rate ofdiffusion of the drug from the resin-drug complex. In addition, theswelling of the ion exchange resin affects the dimensions and shape ofthe ion exchange resin-drug complex. Additionally, the coating can peelfrom the resin-drug complex.

In an effort to reduce the swelling of ion exchange resins, the priorart methods teach treating the ion exchange resin-drug complexes with animpregnating agent, e.g., polyethylene glycol, propylene glycol,mannitol, lactose, methylcellulose or propylene glycol. However, theamount of impregnating agents used to control the swelling is dependenton a variety of factors (e.g., the polymer, the solvent composition, thesalt concentration, the polarity of the solvent, the degree ofcross-linking, the exchange capacity, the strong or weak solvationtendency of the ion groups, the size and extent of the solvation ofcounter ions, the concentration of the external solution, the extent ofthe ionic dissociation of functional groups and so forth) and rangesfrom 15% to 40% by weight. For example, one formulation currently usedincludes AMBERLITE® IR-120 phenylpropanolamine complex with a 35% drugloading treated with polyethylene glycol 4000 at about 30 parts byweight of the solvating agent to 100 parts by weight of the resin toreduce swelling.

Specifically, the use of glycols to control the swelling of ion exchangeresin drug complexes offers many disadvantages. For instance, theconcentration of glycol must be between 15% to 40% by weight to controlthe swelling of the ion exchange resin drug complexes; however, evenwith such concentrations of glycol there remains swelling of the ionexchange resins drug complex. In addition, many compounds are notcompatible with glycols, e.g., penicillin, bicitracine, iodine,potassium iodide, tannic acid, and bismuth salts.

In accordance with the present invention, a method and composition areprovided that include an ion exchange resin treated with from about 0.1%to about 10% by weight of one or more sugar alcohols in contact with oneor more ionic pharmaceutically active compounds. Specifically, the ionexchange resin is a cationic exchange resin treated with less than fivepercent sorbitol to control the subsequent swelling of the drug resincomplex, while maintaining low concentrations of impregnating agents.

For example, the present invention includes a pharmaceutical compositionhaving a pharmaceutically active substance in communication with an ionexchange resin that is treated with from about 0.01% to about 10% byweight of one or more sugar alcohols.

In accordance with the present invention, a method is provided thatreduces the swelling of a pharmaceutical composition by contacting oneor more cationic exchange resin particles with a solution containingfrom about 0.01% to about 10% by weight of sugar alcohol, based on thecombined weight of the sugar alcohol and the one or more ionic exchangeresin particles.

In addition, the present invention includes a method of preparing apharmaceutical ion exchange resin drug complex that does not requirewashing. The method includes contacting one or more grossly wettedcationic exchange resin particles with a drug and adding about 0.1% toabout 10% by weight of one or more sugar alcohols, based on the combinedweight of the sugar alcohol, the drug and the one or more grossly wettedionic exchange resin particles.

BRIEF DESCRIPTION OF THE DRAWINGS

For a more complete understanding of the features and advantages of thepresent invention, reference is now made to the detailed description ofthe invention along with the accompanying figures and in which:

FIG. 1 is a graph of the release profile of Phenylephrine Hydrochloridefrom DRC; and

FIG. 2 is a graph of the release profile for hydrocodone/resin preparedby the present invention this invention.

DETAILED DESCRIPTION OF THE INVENTION

While the making and using of various embodiments of the presentinvention are discussed in detail below, it should be appreciated thatthe present invention provides many applicable inventive concepts thatcan be embodied in a wide variety of specific contexts. The specificembodiments discussed herein are merely illustrative of specific ways tomake and use the invention and do not delimit the scope of theinvention.

To facilitate the understanding of this invention, a number of terms aredefined below. Terms defined herein have meanings as commonly understoodby a person of ordinary skill in the areas relevant to the presentinvention. Terms such as “a”, “an” and “the” are not intended to referto only a singular entity, but include the general class of which aspecific example may be used for illustration. The terminology herein isused to describe specific embodiments of the invention, but their usagedoes not delimit the invention, except as outlined in the claims.

A number of definitions are provided herein to facilitate anunderstanding of the present invention. As used herein, the term“pharmaceutical composition” also describes a solution, suspension,cream, ointment, lotion, capsule, caplet, softgel, gelcap, suppository,enema, elixir, syrup, emulsion, film, granule, gum, insert, jelly, foam,paste, pastille, pellet, spray, troche, lozenge, disk, magma, poultice,or wafer and the like.

As used herein, the term “sugar alcohol,” “organic polyol,” “polyhydricalcohol,” “polyalcohol” or “polyol” are used interchangeably to describenon-toxic C2 to C12 linear or branched hydrocarbon having at least 2hydroxy groups, non-toxic C5 to C12 cyclic or heterocyclic hydrocarbonhaving at least 2 hydroxy groups, e.g., sorbitol, mannitol,polyglycitol, maltitol, lactitol, isomalt, erythritol, glycerin,polydextrose, fructose, maltose xylitol, 1,3-dihydroxypropane inositoland the carbohydrates such as glucose, sucrose.

The term “immediate release” is used herein to describe a releaseprofile to effect the delivery of an active as soon as possible, thatis, as soon as practically made available to a subject, whether inactive form, as a precursor and/or as a metabolite. Immediate releasemay also be defined functionally as the release of over 80% to 90% ofthe active ingredient within about 60, 90, 100 or 120 minutes or less.Immediate release as used herein may also be defined as making theactive ingredient available to the subject regardless of uptake, as somedrugs may never be absorbed by the animal. Immediate releaseformulations of the active on a carrier, such as rolled or compressedbeads, may be formulated such that the surface area is maximized onbeads and the active is exposed immediately. Various immediate releasedosage forms may be designed readily by one of skill in art to achievedrug delivery to the stomach and small intestine, depending upon thechoice of compression, adhesive materials and/or beading.

The terms “extended release,” “controlled release” and “delayed release”as used herein is used to define a release profile to effect delivery ofan active over an extended period of time, defined herein as beingbetween about 60 minutes and about 2, 4, 6 or even 24 hours. Extendedrelease may also be defined functionally as the release of over 80% to90% of the active ingredient after about 60 minutes and about 2, 4, 6 oreven 8 hours. Extended release as used herein may also be defined asmaking the active ingredient available to the subject regardless ofuptake, as some drugs may never be absorbed by the subject. Variousextended and delayed release dosage forms may be designed readily by oneof skill in art as disclosed herein to achieve delivery to both thesmall and large intestines, to only the small intestine, or to only thelarge intestine, depending upon the choice of coating materials and/orcoating thickness. As used herein, “a subject” is a patient, animal,insect, mammal or human, who will benefit from the method of thisinvention.

Pharmaceutical compositions designed for sustained release of activedrugs and taste masking commonly use ion exchange resins particles. Thepresent invention provides controlled-release pharmaceuticalcompositions obtained by complexing a drug with a pharmaceuticallyacceptable ion-exchange resin, treating with a sugar alcohol and in somecases coating the complex with a substance that will act as a barrier tocontrol the diffusion of the drug from its core complex into thegastrointestinal fluids.

For example, the present invention provide a method and composition thatcontrol the swelling of an ion exchange resin particle with one or moreionic pharmaceutically active drug that includes treating with fromabout 0.01% to about 10% by weight of one or more sugar alcohols.

The ion exchange resin particles and pharmacological drug are mixed inan aqueous solution, dried and coated with a water-permeable diffusionbarrier. Sorbitol is added to the ion exchange resin-drug complex tocontrol the swelling of the ion exchange resins drug complex uponcontact with bodily fluids and in-turn reducing the rupturing andpeeling of the coating.

For example, a pharmaceutical composition may have an ionicpharmaceutically active drug that is in communication with an ionexchange resin, wherein the ionic exchange resin has been treated withone or more sugar alcohols, e.g., between about 0.01% and about 10% byweight of based on the combined weight of the one or more sugar alcoholsand the complex particles. Optionally, the pharmaceutical compositionmay be coated with a water-permeable diffusion barrier coating, wherebya selective, prolonged continuous release of the drug is obtainableunder conditions encountered in the gastrointestinal tract.

The present invention includes a pharmaceutical grade cationicion-exchange resin to bind anionic molecules. Ion exchange resins can bedescribed simply as insoluble polymers that contain ionizable groupsdistributed regularly along the polymer backbone. As a consequence, anycounter ion (e.g., drug) associated with the ion exchange resin isionically bound to the ion exchange resin and physically separated fromthe surrounding fluid.

The cationic exchange resin of the present invention may be strongly orweekly acidic and have a variety of functional groups, e.g., weaklyacidic type of resin containing carboxylic acid group, or stronglyacidic type of resins containing sulfonic functional groups. Generally,the carboxylic functional groups are derived from polymers or copolymersof methacrylic acid or polymethacrylic acid and the sulfonic functionalgroups are generally derived from polymers or copolymers of styrene anddivinylbenzene. Other polymeric matrices, organic ion exchange matricesor inorganic ion exchange matrices may be used as suitable ion exchangeresins, e.g., methacrylic, acrylic and phenol formaldehyde.

In addition, ion exchange agents may be used in conjunction with polymermatrices (e.g., cellulosic or dextran) to form a suitable ion exchangeresin. In one embodiment of the present invention, the ionic exchangeresin is a sulfonic acid cationic exchange resin. The present inventionalso uses a sulphonic acid cation exchange resin, which includesphenol-sulphonic acid cation exchange resins and carboxylic-sulphonicacid cation exchange resins. Generally, the resin salt is obtained fromthe reaction of a sulphonic acid with an alkali, e.g., amine. The basicsulphonic acid cation exchange resin has a cation of an amphetamineadsorbed thereon. The skilled artisan will recognize that other cationicexchange resins may be used.

Similarly, a wide range of cationic (for the basic drugs) or anionic(for the acidic drugs) exchange resins can be used to form ion exchangeresin drug complexes. In general, ion-exchangers suitable for use inion-exchange chromatography and for such applications as deionization ofwater are suitable for use as controlled release drug preparations. Forexamples, a model large ion exchange particle includes the cationicexchange resin AMBERLITE® IR-120 having a 20-30 mesh spherical particlesand a model small ion exchange particle resin includes AMBERLITE® XE-69with a 100-200 mesh fractured resin particles of AMBERLITE® IR-120. Theparent resin of AMBERLITE® IR-120 and AMBERLITE® XE-69 is described bythe manufacturer as gel-type divinylbenzene sulfonic acid cationexchange resin that swells in water. Other suitable ion exchange resincandidates include synthetic ion exchange resins with differentpolymeric matrices (e.g., methacrylic, acrylic, phenol formaldehyde),ion exchange agents with cellulosic or dextran polymer matrices andinorganic ion exchange matrices.

The ionic exchange resin includes sulfonic acid cationic exchange resinsand may be made from a polyester polymer containing sulphonic groups,additionally containing units derived from ethylene glycol, unitsderived from tri- and tetraethylene glycol and units derived fromterephthalate, neutralized polyesters having a terminal amine functionalgroup, polyester block copolymers, block copolymers of phthalic andsulphonphthalic acid/ethylene glycol/polymethyl siloxaneα,γ-hydroxypropyl and vinyl acetate/vinyl butylbenzoate/crotonic acid.In addition, the polymer resin may be cross-linked. The cross-linkersinclude poly(2-acrylamido-2-methylpropanesulphonic acid) polymer withone monomer containing at least two olefinic double bonds, e.g.,dipropylene glycol diallyl ether, polyglycol diallyl ether, triethyleneglycol divinyl ether, hydroquinone diallyl ether, tetraallyloxyethanoyl,allyl ether, vinyl ether, a polyfunctional alcohol, tetraethylene glycoldiacrylate, triallylamine, trimethylolpropane diallyl ether,methylenebisacrylamide or divinylbenzene.

Representative pharmaceutical grade ion exchange resins for use inaccordance with the present invention are known to those skilled in theart. For example, pharmaceutical grade ion exchange resins arecommercially available, e.g., the Rohm and Haas company and Dow Corning,e.g., AMBERLITE® IR-20, AMBERLITE® IRP-69, AMBERLITE® IRP-64, AMBERLITE®IRP-58, AMBERLITE® IRC-50, AMBERLITE® IRP-69 and DOW® XYS-40010.00, DOW®XYS-40013.00, etc. The pharmaceutical grade cationic ion-exchange resinsmay include particles of varying size ranges, and as either amonodisperse or a polydisperse mixture. The ion exchange resin particlesmay range in size from 40 to 1500. In one example, the gel-typedivinylbenzene sulfonic acid cation exchange resin AMBERLITE® IRP-69consisting of 100-200 mesh was used.

In general, all acidic and basic drugs, especially those having shortbiological half-lives in the order of up to about 12 hours, arepotential candidates for inclusion in the present invention. Many drugsexist in the free acid, free base, and a salt form. For example, a basedrug may exist as either a free base form or a salt form, e.g., a basedrug; lidocaine has an amine free base form and a hydrochlorideacid-addition salt form. Conversely, an acid drug may exist in either afree acid form or in the form of a salt made by reacting the free acidwith a base, e.g., salicylic acid exists as a salt, typically as sodiumsalicylate. For example, a cationic resin interacts with the basicnitrogen group of an organic molecule. Generally, the functional groupson the drug dictate the interaction with the ion exchange resin, andthus, influence the adsorption and the elution characteristics of thedrug. A substantial portion of the active drug is adsorbed within thepolymer matrix of the ion exchange resin and elutes therefrom. Tocontrol the elution rate the size of the particle and the size of theadsorbed drug may be altered by modifying the cross linkage of the ionexchange resin.

Suitable pharmaceutically active drugs include narcotic analgesics,(e.g., codeine, dihydrocodeine, hydromorphone, morphine, pentazocine andpropoxyphene), sympathomimetics, (e.g., norephedrine andpseudoephedrine), antitussives, (e.g., dextromethorphan, gauifenesin),analgesics, (e.g., aspirin and tramadol), antiemetics, (e.g.,metoclopramide), anticholinergics, (e.g., atropine, ipratropium bromideand scopolamine), muscle relaxants, (e.g., cyclobenzaprine andpapaverine), bronchodilators, (e.g., salbutamol, terbutaline andtheophylline), antibiotics, (e.g., amoxycillin, ampicillin, azlocillin,bacampicillin, cefamandole, cefonicid, cefotaxime, cefotetan, cefoxitin,ceftriaxone, mezlocillin and piperacillin), antidepressants, (e.g.,bupropion, nomifensine, and nortriptyline), antiasthmatics, (e.g.,cromolyn), antineoplastics, (e.g., tamoxifen), antiepileptics, (e.g.,valproic acid and phenvtoin), cardiovascular agents, (e.g., propranolol)phenylephrine, and gauifenesin. Acid addition salts or, if appropriate,alkali or alkaline earth metal salts of the above drugs would beparticularly suitable for use in the present invention.

Specific examples of suitable pharmaceutically active drugs include, butare not limited to, dehydrocholic acid, diflunisal, ethacrynic acid,fenoprofen, furosemide, gemfibrozil, ibuprofen, naproxen, phenytoin,probenecid, sulindac, theophylline, salicylic acid, acetylsalicylicacid, acetophenazine, amitriptyline, amphetamine, benztropine,biperiden, bromodiphenhydramine, brompheniramine, carbinoxamine,chlorcyclizine, chlorpheniramine, chlorphenoxamine, chlorpromazine,clemastine, clomiphene, clonidine, codeine, cyclizine, cyclobenzaprine,cyproheptadine, desipramine, desloratadine, dexbrompheniramine,dexchlorpheniramine, dextroamphetamine, dextromethorphan, dicyclomine,diphemanil, diphenhydramine, doxepin, doxylamine, ergotamine,fluphenazine, haloperidol, hydrocodone, hydroxychloroquine, hydroxyzine,hyoscyamine, imipramine, levopropoxyphene, loratadine, maprotiline,meclizine, mepenzolate, meperidine, mephentermine, mesoridazine,methadone, methdilazine, methscopolamine, methysergide, metoprolol,nortriptylene, noscapine, nylindrin, orphenadrine, papaverine,pentazocine, phendimetrazine, phentermine, phenylephrine,phenylpropanolamine, pyrilamine, tripelennamine, triprolidine,promazine, propoxyphene, propanolol, pseudoephedrine, pyrilamine,quinidine, scopolamine, dextromethorphan, chlorpheniramine, codeine,aminocaproic acid, aminosalicylic acid, hydromorphone, isoxsuprine,levorphanol, melphalan, morphine, nalidixic acid, paraaminosalicylicacid and mixtures and combinations thereof.

Examples of acidic and basic drugs that may be used with the presentinvention include phenylpropanolamine (PPA), dextromethorphan, ephedrin,pseudoephedrine, paraamino salicyclic acid, acetyl salicylic acid,phentermine (phenyl-tertiary-butyl-amine) and acetaminophen. The skilledartisan will recognize the variety of drugs and resins that may be usedand the modifications to alter the polymer, copolymer, cross linkingagent that may be used to alter the characteristics of the drug-resincomplex. The pharmaceutically active compounds useful in the practice ofthe present invention include antihistamines, decongestants,antitussives and/or expectorants. Other drugs for use with the presentinvention include, but are not limited to non-steroidalanti-inflammatory drugs (NSAIDs) and other analgesic drugs, e.g.,acetaminophen and phenacetin. These materials are incorporated into theimmediate or controlled release formulations of the invention in amountsgoverned by the desired release characteristics of the material in suchexcipient base and such that conventional dosages comply with applicableFDA or other regulations. The drug may be loaded in a specificconcentration to allow the specific release of the drug over a giventime range. In general, the maximum concentration of bound drug may bein excess of about 60%; however, ranges between about 1% and about 50%are contemplated with the present invention.

The present invention may be used to deliver bioactive agents includingpharmaceuticals and drugs, bioactive synthetic organic molecules,genetic materials, proteins, peptides, polypeptides, vitamins, steroids,polyanionic agents, genetic material, and diagnostic agents. Bioactivevitamins, steroids, proteins, peptides and polypeptides can be ofnatural origin or synthetic. Exemplary polyanionic agents include, butare not limited to, sulphated polysaccharides, negatively charged serumalbumin and milk proteins, synthetic sulphated polymers, polymerizedanionic surfactants, and polyphosphates. Suitable diagnostic agentsinclude, but are not limited to, dyes and contrast agents for use inconnection with magnetic resonance imaging, ultrasound or computedtomography of a patient. In addition, the pharmaceutically active drugmay be any pesticide known to the skilled artisan for use in theextended release pesticide control of insects, rodents and other pests.

Suitable genetic material includes nucleic acids, nucleosides,nucleotides, and polynucleotides that can be either isolated genomic,synthetic or recombinant material; either single or double stranded; andeither in the sense or antisense direction, with or withoutmodifications to bases, carbohydrate residues or phosphodiesterlinkages. Exemplary sources for the genetic material include, but arenot limited to, deoxyribonucleic acids (DNA), ribonucleic acids (RNA),complementary DNA (cDNA), messenger RNA (mRNA), ribosomal RNA (rRNA),short interfering RNA (siRNA), ribozymes, and mixed duplexes andtriplexes of RNA and DNA.

Genetic materials are genes carried on expression vectors including butnot limited to helper viruses, plasmids, phagemids, cosmids, and yeastartificial chromosomes. The genetic material suitable for the presentinvention is capable of coding for at least a portion of a therapeutic,regulatory, and/or diagnostic protein. Moreover, genetic materials canpreferably code for more than one type of protein. For example, abioactive agent may include plasmid DNA having genetic material encodingtherapeutic protein and a selectable or diagnostic marker to monitor thedelivery of the plasmid DNA, e.g., pDsRed-human insulin promoter. Suchproteins include, but are not limited to, histocompatibility antigens,cell adhesion molecules, growth factors, coagulation factors, hormones,insulin, cytokines, chemokines, antibodies, antibody fragments, cellreceptors, intracellular enzymes, transcriptional factors, and toxicpeptides capable of eliminating diseased or malignant cells. Othergenetic materials that could be delivered by this technique includedadenovirus, adeno-associated virus, retrovirus, lentivirus, RNA, siRNA,or chemicals that selectively turn on or off specific genes, such aspolyamides or peptide fragments. Modifications to wild-type proteinsresulting in agonists or antagonists of the wild type variant fall inthe scope of this invention. The genetic material may also include atissue-specific promoter or expression control sequences such as atranscriptional promoter, an enhancer, a transcriptional terminator, anoperator or other control sequences.

Examples of active agents for use with the present invention include,but are not limited to, hormone products such as vasopressin andoxytocin and their derivatives, glucagon and thyroid agents as iodineproducts and anti-thyroid agents; cardiovascular products as chelatingagents and mercurial diuretics and cardiac glycosides; respiratoryproducts as xanthine derivatives (theophylline and aminophylline);anti-infectives as aminoglycosides, antifungals (e.g., amphotericin),penicillin and cephalosporin antibiotics, antiviral agents (e.g.,zidovudine, ribavirin, amantadine, vidarabine and acyclovir),antihelmintics, antimalarials, and antituberculous drugs; biologicalssuch as antibodies (e.g., antitoxins and antivenins), vaccine antigens(e.g., bacterial vaccines, viral vaccines, toxoids); antineoplastics(e.g., nitrosoureas, nitrogen mustards, antimetabolites (fluorouracil,hormones, progestins and estrogens agonists and/or antagonists); mitoticinhibitors (e.g., etoposide and/or vinca alkaloids),radiopharmaceuticals (e.g., radioactive iodine and phosphorus products);and interferon, hydroxyurea, procarbazine, dacarbazine, mitotane,asparaginase and cyclosporins, including mixtures and combinationsthereof.

Other suitable therapeutics include, but are not limited to:thrombolytic agents such as urokinase; coagulants such as thrombin;antineoplastic agents, such as platinum compounds (e.g., spiroplatin,cisplatin, and carboplatin), methotrexate, adriamycin, taxol, mitomycin,ansamitocin, bleomycin, cytosine arabinoside, arabinosyl adsnine,mercaptopolylysine, vincristine, busulfan, chlorambucil, melphalan(e.g., PAM, L-PAM or phenylalanine mustard), mercaptopurine, mitotane,procarbazine hydrochloride dactinomycin (actinomycin D),daunorubicinhydrochloride, doxorubicin hydrochloride, mitomycin,plicamycin (mithramycin), aminoglutethimide, estramustine phosphatesodium, flutamide, leuprolide acetate, megestrol acetate, tamoxifencitrate, testolactone, trilostane, amsacrine (m-AMSA), asparaginase(L-asparaginase), erwinaasparaginase, etoposide (VP-16), interferonalpha-2a, interferon alpha-2b, teniposide (VM-26), vinblastine sulfate(VLB), vincristine sulfate, bleomycin, bleomycin sulfate, methotrexate,adriamycin, and arabinosyl; blood products such as parenteral iron,hemin; biological response modifiers such as muramyldipeptide,muramyltripeptide, microbial cell wall components, lymphokines (e.g.,bacterial endotoxin such as lipopolysaccharide, macrophage activationfactor), sub-units of bacteria (such as Mycobacteria, Corynebacteria),the synthetic dipeptide N-acetyl-muramyl-L-alanyl-D-isog-lutamine;anti-fungalagents such as ketoconazole, nystatin, griseofulvin,flucytosine (5-fc), miconazole, amphotericin B, ricin, and beta-lactamantibiotics (e.g., penicillin, ampicillin, sulfazecin); hormones such asgrowth hormone, PDGF, EGF, CSF, GM-CSF, melanocyte stimulating hormone,estradiol, beclomethasone dipropionate, betamethasone, betamethasoneacetate and betamethasone sodium phosphate,vetamethasonedisodiumphosphate, vetamethasone sodium phosphate,cortisone acetate, dexamethasone, dexamethasone acetate, dexamethasonesodium phosphate, flunsolide, hydrocortisone, hydrocortisone acetate,hydrocortisone cypionate, hydrocortisone sodium phosphate,hydrocortisone sodium succinate, methylprednisolone, methylprednisoloneacetate, methylprednisolone sodium succinate, paramethasone acetate,prednisolone, prednisoloneacetate, prednisolone sodium phosphate,prednisolone rebutate, prednisone, triamcinolone, triamcinoloneacetonide, triamcinolone diacetate, triamcinolone hexacetonide andfludrocortisone acetate; vitamins (e.g., vitamin C, E, A, and K),ascyanocobalamin, neinoic acid, retinoids and derivatives such asretinolpalmitate, and alpha-tocopherol(s); peptides (e.g., T cellepitopes such as MAGE, GAGE, DAGE, etc.); proteins, such as manganesesuper oxide dimutase, alcohol dehydrogenase, nitric oxide synthase;enzymes such as alkaline phosphatase; anti-allergic agents such asamelexanox; anti-coagulation agents such as phenprocoumon and heparin;circulatory drugs such as propranolol; metabolic potentiators suchasglutathione; antituberculars such as paraaminosalicylic acid,isoniazid, capreomycin sulfate cycloserine, ethambutol hydrochlorideethionamide, pyrazinamide, rifampin, and streptomycin sulfate;antivirals such as acyclovir, amantadine azidothymidine (AZT orZidovudine), Ribavirin and vidarabine monohydrate (adenine arabinoside,ara-A); antianginals such asdiltiazem, nifedipine, verapamil, erythrityltetranitrate, isosorbidedinitrate, nitroglycerin (glyceryl trinitrate)and pentaerythritoltetranitrate; anticoagulants such as phenprocoumon,heparin; antibiotics such as dapsone, chloramphenicol, neomycin,cefaclor, cefadroxil, cephalexin, cephradine erythromycin, clindamycin,lincomycin, amoxicillin, ampicillin, bacampicillin, carbenicillin,dicloxacillin, cyclacillin, picloxacillin, hetacillin, methicillin,nafcillin, oxacillin, penicillin G, penicillin V, ticarcillin rifampinand tetracycline; antiinflammatories such as difunisal, ibuprofen,indomethacin, meclofenamate, mefenamic acid, naproxen, oxyphenbutazone,phenylbutazone, piroxicam, sulindac, tolmetin, aspirin and salicylates;antiprotozoans such as chloroquine, hydroxychloroquine, metronidazole,quinine and meglumine antimonate; antirheumatics such as penicillamine;narcotics such as paregoric; opiates such as codeine, heroin, methadone,morphine and opium; cardiac glycosides such as deslanoside, digitoxin,digoxin, digitalin and digitalis; neuromuscular blockers such asatracurium besylate, gallamine triethiodide, hexafluorenium bromide,metocurine iodide, pancuronium bromide, succinylcholine chloride(suxamethonium chloride), tubocurarine chloride and vecuronium bromide;sedatives (hypnotics) such as amobarbital, amobarbital sodium,aprobarbital, butabarbital sodium, chloral hydrate, ethchlorvynol,ethinamate, flurazepam hydrochloride, glutethimide, methotrimeprazinehydrochloride, methyprylon, midazolam hydrochloride, paraldehyde,pentobarbital, pentobarbital sodium, phenobarbital sodium, secobarbitalsodium, talbutal, temazepam and triazolam; local anesthetics such asbupivacaine hydrochloride, chloroprocaine hydrochloride,etidocainehydrochloride, lidocaine hydrochloride, mepivacainehydrochloride, procainehydrochloride and tetracaine hydrochloride;general anesthetics such asdroperidol, etomidate, fentanyl citrate withdroperidol, ketaminehydrochloride, methohexital sodium and thiopentalsodium; and radioactive particles or ions such as strontium, iodiderhenium and yttrium, and combinations and mixtures thereof.

The ion exchange resin of the present invention is treated with one ormore sugar alcohols. The ion exchange resin may be treated before,during or after the addition of the pharmaceutical drug and formation ofthe drug-resin complex. Additionally, the drug-resin complex may betreated before, during or after the addition of a coating to thedrug-ion exchange resin complex. The sugar alcohol may be added as asolid, liquid, gas or gel. The sugar alcohols may be in an aqueoussolution or mixtures containing varying amounts of organic compoundsknown to those skilled in the art. Furthermore, when more than one sugaralcohol is used the sugar alcohols may be similar or different dependingon the particular application and conditions. In some embodiments, theionic exchange resin may be treated with between about 1% to 10% byweight of sorbitol, based on the combined weight of the sorbitol and thedrug-resin particles. Other concentrations of sorbitol may be usedincluding about 0.1% to about 5% by weight.

The sugar alcohols may be of many types known to persons of skill in theart to control the swelling of the pharmaceutical grade ion exchangedrug-resins complex. The sugar alcohol is generally sorbitol; however,polyhydric alcohols such as mannitol; sorbitol; xylitol; maltitol;lactitol, 1,3-dihydroxypropane, or other non-toxic C2 to C12 linear orbranched hydrocarbon having at least 2 hydroxy groups known to theskilled artisan may be used. Additionally, non-toxic C5 to C12 cyclic orheterocyclic hydrocarbon having at least 2 hydroxy groups (e.g.,inositol and the carbohydrates such as glucose, sucrose) may be used aswell. The sugar or the sugar alcohol present in the solution has amolecular weight of from 90 to 550, and especially from molecularweights of between 150 and 370. The sugars are monosaccharides ordisaccharides and reduced monosaccharides or disaccharides andsubstituted monosaccharides or disaccharides. Suitable sugars/sugaralcohols are sucrose, dextrose, maltose, fructose, lactose, mannitol,sorbitol or xylitol.

The general method for preparing controlled release cationic exchangeresin drug complex using the present invention involves: (i) preparationof an ion exchange resin drug complex; (ii) treating the ion exchangeresin drug complex with a suitable sugar alcohol; and (iii) drying thetreated ion exchange resin drug complex. The ion exchange resin drugcomplex may be optionally coated with a water-permeable diffusionbarrier.

Preparing the ion exchange resin drug complex from the ion exchangeresin is generally includes mixing the ion exchange resin with asolution in the presence of a polyalcohol and allowing sufficient timefor loading. The resin/fluid slurry is filtered. Unlike methodscurrently used in the art, it is not necessary to wash the ionicexchange resin-complex after the additions. Furthermore, the presentinvention provides for equilibrium redistribution by allowing theunbound drug, the free drug or any water-soluble swelling agent toredistribute themselves in equilibrium. The equilibrium distributionallows the free drug to be further taken up by the resin.

For example, the present invention includes a method of making apharmaceutical composition by contacting one or more ion exchange resinparticles and one or more pharmaceutically active drugs to form acationic exchange resin pharmaceutically active drugs complex. The ionicexchange resin drug complex is treated to control the swelling of theresin by adding one or more sugar alcohols. The one or more sugaralcohols make up between about 0.01% and about 10% by weight of one ormore sugar alcohols, based on the combined weight of the sugar alcohol,the drug(s) and the one or more ionic exchange resin particles. Thecomposition may then be formulated into the desired pharmaceuticalcomposition delivery forms.

Generally, the present invention is formulated into a liquid, gel,tablet, caplet, or capsule; however, other pharmaceutical compositiondelivery forms may be used while taking advantage of the presentinvention. Other agents may be added, including binders, lubricants,diluents, disintegrating agents, coloring agents, sweeteners, flavoringagents, preservatives and flow-inducing agents. The tablets can becompressed, multiple compressed, tablet triturates or coated, e.g.,enteric coating, sugar coating, or film coating. When in the form of aliquid, the liquid oral dosage may be in the form of aqueous andnon-aqueous solutions, emulsions, suspensions, and solutions granules,containing suitable, emulsifying agents, solvents, preservatives,suspending agents, diluents, sweeteners, coloring agents, and flavoringagents.

The present invention provides a method of preparing a resin drugcomplex without washing. Preparing the ion exchange resin drug complexfrom the ion exchange resin includes mixing the ion exchange resin witha solution and allowing sufficient time for loading. The resin/fluidslurry is filtered. Unlike methods currently used in the art, it is notnecessary to wash the ionic exchange resin-complex.

The present invention also provides a method of controlling the swellingof a pharmaceutical composition by contacting one or more cationicexchange resin particles with about 0.01% to about 10% by weight ofsugar alcohol, based on the combined weight of the sugar alcohol, thedrug(s).

In accordance with the present invention, it is necessary to combine thesugar alcohol with the ion exchange resin to form a mixture (e.g.,slurry). Generally, the mixture is an aqueous solution; however, othersolutions, compositions or mixtures are acceptable. The ratio of ionexchange resin to sugar alcohol is from about 1:1 to about 50:1, i.e.,from about 1 gram of resin per gram of the sugar alcohol to about 1 gramof resin per 20 mg. of polyol. Other ratios may be used depending on themethod of incorporation and the particular sugar alcohol and resin,e.g., about 1:0.01 to about 5:0.01, about 0.01:1 to about 0.01:5, andcombinations thereof. In Example I, the ratio of the amount of ionexchange resin in suspension to the amount of sugar alcohol is about1.7:1 (e.g., 300 grams of resin per 175 grams of molecule) with most ofthe sugar alcohol not remaining in the product. In another example, theconcentration of the sugar alcohol is between about 1% and 10% byweight, i.e., about 10 mg to about 100 mg of molecule.

EXAMPLE I

Resin 300 g Drug 300 g 70% Sorbitol 250 mL Purified Water 750 mL

In Example I, the water, sorbitol, drug and resin are slurried togetherand sufficient time is allowed for the drug to load onto the resin. Whenthe loading operation is completed the components of the slurry areseparated (e.g., filtered or centrifuged) into liquid and solidfractions. Because the sugar alcohol is highly water soluble most of thesugar alcohol remains in the aqueous phase, leaving about 4% sorbitol inthe solids. The solids are not washed but are dried to yield materialsuitable for coating.

EXAMPLE II

Resin 300.0 g Drug 300.0 g Sorbitol  7.5 g Purified Water 992.5 mL

In Example II, the water, drug and resin are slurried together andsufficient time is allowed for the drug to load onto the resin. When theloading operation is completed the slurry is separated (e.g., filteredor centrifuged) into liquid and solid fractions. The liquid fraction isdiscarded. The solid fraction is not washed but is dried. Sorbitol isdissolved in 100 grams water, added to the dried drug resin complex andthe drug resin complex is allowed to absorb the sorbitol solution. Thetreated resin may then be dried and coated.

To form the cationic exchange resin drug complex it is necessary tocombine an ion exchange resin with one or more molecules, e.g., one ormore ionic drug compounds. The adsorption of molecules to the surface ofa resin is well known to persons of skill in the art. In addition, theionic drug molecule may be attached to a linker that allows attachmentof the drug to the ion exchange resin via the linker. The combination ofion exchange resins and drug may be in the form of a slurry or othermixture, depending on the particular application. In addition, a coatingmay be applied to the drug-resin complex. The mixture (e.g., anadmixture of slurry of the ion exchange resin, the drug and the sugaralcohol) may be dried to remove the water. The drying may be carried outusing methods known to the skilled artisan including conventional means,i.e., filtered, dried over a purge of nitrogen, under vacuum, in a fluidbed, in an oven, etc.

The present invention optionally includes a pharmacologically activedrug-resin complex coated to prolong the continuous release of drugsunder harsh biological conditions, e.g., such as those encountered inthe gastrointestinal tract. Conventional coating solvents (e.g.,ethanol, a methylene chloride/acetone mixture or other component knownto the skilled artisan) or aqueous based coatings and procedures can beemployed to coat the ion exchange resin drug complex. In oneillustrative example, air suspension spray coating techniques may becarried out using a Wurster coating apparatus. However, other techniquesmay be used to coat the particle, including other types of fluid bedspray, coacervation, solvent evaporation or other methods known topersons of skill in the art. Generally, the coating is applied to thedrug-resin complex. Alternatively, the coating can be applied to theresin before complexing with the drug.

Another example of a coated particle of the present invention provides aselective, prolonged continuous release of pharmacologically activedrugs, under conditions such as those encountered in thegastrointestinal tract by the application of a diffusion barrier coatingto an ion exchange drug-resin complex treated with a solvating agent.Another prolonged release formulation of the present invention includesthe addition of a second ionic substance (e.g., a combination drug, adye, a dispersing agent or the like) having the same ionic charge as thedrug on the drug-resin complex by employing the second ionic substancein the ion form of an exchange resin complex. The manufacture of aformulation of any drug for liquid dosage usage requires that the finalformulation have the drug dissolved or suspended in a liquid thatpossesses extended shelf-life stability and exhibits no change in activedrug dosage level over a period of time and has acceptable taste. Thus,to prepare a liquid formulation of any type drug, it may be necessary toemploy extenders such as water or syrup and to add flavors, sweeteners,thickening agents, dyes and the like. To control the dissolution profileof the formulation versus the dissolution profile of the same drug inwater, the coated particles may also be included in the presence ofionic substances bearing the same ionic charge as the sustained releasedrug present in the formulation as a coated drug-resin complex. Thesecond ionic material need not be coated with the water-permeablediffusion barrier coating.

The water-permeable diffusion barrier coating materials can be any ofthe conventional synthetic or natural film-forming materials withdiffusion barrier properties and with no inherent pharmacological ortoxic properties. For example, ethylcellulose, a water insolublefilm-forming agent, may be used as a diffusion barrier membranematerial. A plasticizer, (e.g., Durkex 500 vegetable oil) may be used toimprove the film forming characteristics of ethylcellulose and/or toalter the permeability characteristics of the film. The amount ofcoating used depends on the degree of drug release prolongation desiredand is a function of particle size, drug solubility, film permeabilityand other factors. By varying the amount of coating, and/or by blendingcoated drug-resin complex with uncoated drug-resin complex, and/orblending different coatings, it is possible to selectively modify thepreparation's drug dissolution profile as desired.

In general, the major components of the coating should be insoluble in,and permeable to, water. Alternatively, a water-soluble substance, suchas methyl cellulose may be incorporated, to alter the permeability ofthe coating, or an acid-insoluble, base-soluble substance to act as anenteric coating may be used. The water-permeable diffusion barrier willgenerally include a water insoluble material such as a wax, a fattyalcohol, shellac, zein, shellac, polyvinylpyrrolidone, a water insolublecellulose derivative, ethyl cellulose, a polymethacrylate, or methylcellulose. The coating materials may be applied as a solution orsuspension in an aqueous fluid or as a solution in organic solvents. Insome instances, the present invention may include a water-permeablediffusion barrier in contact with at least a portion of the ionicpharmaceutically active drug in communication with an ionic exchangeresin. Example III is a water-permeable diffusion barrier coated drugresin complex that includes:

EXAMPLE III

Drug Resin Complex 2000 g Ethylcellulose  300 g Ethyl acetate 5700 g

The drug resin complex was placed in a fluid-bed coating apparatus andfluidized with intake air. The ethylcellulose was dissolved in the ethylacetate and applied at a rate of about 20-25 grams per minute until 6000grams had been applied. Fluidization was continued with the heated airfor an additional ten minutes after termination of the application ofthe coating solution. Example IV is another water-permeable diffusionbarrier coated drug resin complex that includes:

EXAMPLE IV

Drug Resin Complex 2000 g Ethylcellulose  119 g Myvacet  11 g Ethanol2470 g

The drug resin complex was placed in a fluid-bed coating apparatus andfluidized with intake air. The Myvacet was dissolved in the ethanol andthe ethylcellulose was dissolved in the Myvacet solution and applied ata rate of 20-25 g/minute until 2600 g of coating solution had beenapplied.

The present invention may be incorporated into a pharmaceuticalcomposition and include immediate release, extended release or delayedrelease compositions. The present invention relates to oraladministration of cationic exchange resin drug complex, although otherdelivery methods are also contemplated, e.g., topical, rectal,injectable, subcutaneous, vaginal or nasal administration. Thepharmaceutical compositions of the present invention can take the formof tablets, powders, capsules, gels, hydro-gels, solids, lyophilizedsuspensions, liquid suspensions or other conventional dosage forms. Thepresent pharmaceutical composition may also be provided in a variety ofdosage forms, e.g., solution, suspension, cream, ointment, lotion,capsule, caplet, softgel, gelcap, suppository, enema, elixir, syrup,emulsion, film, granule, gum, insert, jelly, foam, paste, pastille,pellet, spray, troche, lozenge, disk, magma, poultice, or wafer and thelike. In addition the resin-drug complex of the present invention issuitable for dosages varying over a wide range, e.g., from about 0.01 toabout 2000 mg, depending on the nature of the drug, resin and itsintended usage.

In addition, the present invention may include other additivesconventionally used in pharmaceutical compositions and known to those ofskill in the art, e.g., anti-adherents, anti-sticking agents, glidants,flow promoters, lubricants, talc, magnesium stearate, fumed silica,micronized silica, surfactants, waxes, stearic acid, stearic acid salts,stearic acid derivatives, starch, hydrogenated vegetable oils, sodiumbenzoate, sodium acetate, leucine and magnesium lauryl sulfate.

In accordance with the present invention is a method of reducing thehandling of a pharmaceutical composition during preparation bycontacting one or more grossly wetted cationic exchange resin particleswith an active drug and adding about 0.1% to about 5% by weight of sugaralcohol, based on the combined weight of the sugar alcohol, drugsubstance and the one or more grossly wetted ionic exchange resinparticles. Additionally, the pharmaceutical composition can be coatedwith a water-permeable diffusion barrier.

EXAMPLE V

Purified Water USP 45.26 Kg Sorbitol USP  9.59 Kg AMBERLITE IRP69 16.50Kg Dextromethorphan HBr USP 16.50 Kg

In Example V, the water, sorbitol, drug and resin are slurried togetherand sufficient time allowed for the drug to load onto the resin. Whenthe loading operation is completed the slurry is separated (e.g.,filtered or centrifuged) into liquid and solid fractions. Because thesugar alcohol is highly water soluble most of the sugar alcohol remainsin the aqueous phase leaving with about 4% sorbitol in the solids. Thesolids are not washed but are dried to yield material suitable forcoating.

EXAMPLE VI

Purified Water USP 41.15 Kg Sorbitol USP (70%) 13.70 Kg AMBERLITE IRP6916.50 Kg Pseudoephedrine HCl 16.50 Kg

In Example VI, the Water, sorbitol, drug and resin are slurried togetherand time allowed for the drug to load onto the resin. When the loadingoperation is completed the slurry is separated (e.g., filtered orcentrifuged) into liquid and solid fractions. Because the sugar alcoholis highly water soluble, most of the sugar alcohol remains in theaqueous phase leaving with about 4% sorbitol in the solids. The solidsare not washed but are dried to yield material suitable for coating.Product from examples V and VI were coated in fluidized bed processingunit using ethylcellulose plasticized with dibutyl sebacate fromacetone/alcohol solution. It is recognized by the skilled artisan thatthe release profile may be modified by varying the coating level.

Release profiles for Examples V and VI are shown:

Time Example V Example VI  30 min 43% 50%  60 min 47% 55% 180 min 53%63% 360 min 57% 68%

Table I is an Exemplary table of possible pharmaceutical compounds thatmay be used in conjunction with available resins. Those skilled in theart will recognize that other compounds may be used with the presentinvention and that compounds may be modified or the particular chemicalgroup modified in a compound to allow the use of that compound with thepresent invention.

TABLE I Pharmaceutical compounds and drug resins: PharmaceuticalCompounds Resins Codeine, Dihydrocodeine, Hydromorphone, AMBERLITE ®IR-20 Morphine, Pentazocine and Propoxyphene Norephedrine andPseudoephedrine Dextromethorphan, gauifenesin, phenylephrine Aspirin andTramadol, naprisin Metoclopramide Atropine, Ipratropium Bromide andScopolamine AMBERLITE ® IRC-50 Cyclobenzaprine and PapaverineSalbutamol, Terbutaline and Theophylline Amoxycillin, Ampicillin,Azlocillin, Bacampicillin, Cefamandole, Cefonicid, Cefotaxime,Cefotetan, Cefoxitin, Ceftriaxone, Mezlocillin and PiperacillinBupropion, Nomifensine, and Nortriptyline AMBERLITE ® IRP-58 CromolynValproic Acid and Phenvtoin Propranolol Tamoxifen Dehydrocholic Acid,Diflunisal, Ethacrynic Acid, AMBERLITE ® IRP-64 Fenoprofen, Furosemide,Gemfibrozil, Ibuprofen, Naproxen, Phenytoin, Probenecid, Sulindac,Theophylline, Salicylic Acid, Acetylsalicylic Acid, Acetophenazine,Amitriptyline, Amphetamine, Benztropine, Biperiden,Bromodiphenhydramine, Brompheniramine, Carbinoxamine, Chlorcyclizine,AMBERLITE ® IRP-69 Chlorpheniramine, Chlorphenoxamine, Chlorpromazine,Clemastine, Clomiphene, Clonidine, Codeine, Cyclizine, Cyclobenzaprine,Cyproheptadine, Desipramine, Dexbrompheniramine, Dexchlorpheniramine,Dextroamphetamine, Dicyclomine, Diphemanil, Diphenhydramine, Doxepin,Doxylamine, Ergotamine, AMBERLITE ® XE-69 Fluphenazine, Haloperidol,Hydrocodone, Hydroxychloroquine, Hydroxyzine, Hyoscyamine, Imipramine,Levopropoxyphene, Maprotiline, Meclizine, Mepenzolate, Meperidine,Mephentermine, Mesoridazine, Methadone, Methdilazine, Methscopolamine,Methysergide, Metoprolol, Nortriptylene, Noscapine, AMBERLITE ® IR-120Nylindrin, Orphenadrine, Papaverine, Pentazocine, Phendimetrazine,Phentermine, Phenylpropanolamine, Pyrilamine, Tripelennamine,Triprolidine, Promazine, Propoxyphene, Propanolol, Pseudoephedrine,Pyrilamine, Quinidine, Scopolamine, Chlorpheniramine, Codeine,Aminocaproic Acid, Aminosalicylic Acid, DOW ® XYS-40013.00Hydromorphone, Isoxsuprine, Levorphanol, Melphalan, Morphine, NalidixicAcid, Paraaminosalicylic Acid Phenylpropanolamine (PPA),Dextromethorphan, Ephedrin, Pseudoephedrine, Paraamino Salicyclic Acid,Acetyl Salicylic Acid, Phentermine (Phenyl-Tertiary- Butyl-Amine) andAcetaminophen Acetominophen and Phenacetin DOW ® XYS-40010.00

The samples were evaluated under conditions that simulate thoseencountered in the gastrointestinal tract. The samples were evaluatedusing USP Dissolution Apparatus 2 and Simulated Gastric Fluid USP.Additional tests were applied as deemed suitable, i.e., USP Apparatus 4using Simulated Gastric Fluid or selected buffer solutions. The changesin absorption at the selected wavelength as a function of time wasrecorded as the drug was released from a drug-resin complex sample.

Table II is a comparison of the release curves in simulated gastricconditions for the present invention and resin complexes made by methodsused in the art. In Table II, the percent release is charted as afunction of time for the present invention (A), a sample made using thepost treatment protocol under U.S. Pat. No. 4,847,077 (B) and a samplemade using no treatment under the protocol of U.S. Pat. No. 4,996,047(C). The data represented in Table II demonstrates that while high drugloading can be used to prepare coated, slow release drug resin complex,the use of higher levels of treatment under the '077 patent result in aslower, better controlled release profile. It also shows that much lowerlevels of treating agent as prepared by the present invention result incomparable, lower release rates.

TABLE II % Released Time (hours) A B C 0.1 14.3 18.3 19.3 0.5 29.3 29.132.5 1 33.9 33.1 37.5 2 37.9 36.9 41.6 3 40.3 39.1 44.1 4 42.1 41.0 45.65 43.6 42.3 47.2 6 44.8 43.7 48.8 7 45.9 44.3 49.7 8 46.9 45.3 50.4 947.8 46.2 51.1 10 48.6 47.1 52.1

Table III is a comparison of the relative amounts and combinations ofdrug and resin complexes of the present invention. Table III is only anexemplar table and the skilled artisan will recognize the numerouscombinations of drug and resin complexes.

mgs Drug Aspirin/ PropoxyPhene/ Naproxen/ DextroMethorphan/PseudoePhedrine/ Resin Codeine acetaminophen Gauifenesin CarbinoxaminePhenylephrine IRP-69 50-1000 50-1000 50-1000 50-1000 50-1000 80-2000IR-20 50-1000 50-1000 50-1000 50-1000 50-1000 80-2000 IRC-50 50-100050-1000 50-1000 50-1000 50-1000 80-2000 IRP-58 50-1000 50-1000 50-100050-1000 50-1000 80-2000 IRP-64 50-1000 50-1000 50-1000 50-1000 50-100080-2000 IRP-69 50-1000 50-1000 50-1000 50-1000 50-1000 80-2000 XE-6950-1000 50-1000 50-1000 50-1000 50-1000 80-2000 IR-120 50-1000 50-100050-1000 50-1000 50-1000 80-2000 XYS-40013.00 50-1000 50-1000 50-100050-1000 50-1000 80-2000 XYS-40010.00 50-1000 50-1000 50-1000 50-100050-1000 80-2000

In addition to pharmaceutically active drugs used in conjunction withavailable resins, the inventors have contemplated the use of other knownactive compounds with the present invention, e.g., herbicides,fungicides, insecticides, acaricides, nematicides, bird repellants,plant nutrients and agents that improve soil structure.

In addition, the present invention provides a method to enhance theefficiency of preparing ion exchange resins and pharmaceutically activedrug resin-compound preparations. Unlike the present invention, theprior art describes forming complexes between ion exchange resins andvarious compounds by dissolving the compound of interest in a media andsuspending the ion exchange resin in that preparation. After a period,the dissolved compound binds to the ion exchange resin to form acompound/resin complex. The media and any remaining unbound compound areseparated from the compound/resin complex by filtering or othermechanical methods. The compound/resin complex is then washed to removefree compound and dried. The compound/resin complex can then be treatedas necessary to swell the complex and coated with a rate controllingmembrane to control the rate of release of the compound from the resinwhen exposed to regenerating media.

The present inventors recognized that in the procedures currently usedin the art to prepare pharmaceutical compositions, there are numeroussteps in the loading procedures (e.g., loading procedure, dry process,treatment procedure and/or the final drying process) that limit theefficiency of the pharmaceutical composition due to pharmaceuticallyactive drugs loss, e.g., some portion of the pharmaceutically activedrugs of interest may be removed during filtering and/or washing of thepharmaceutical composition. Generally, the pharmaceutically active drugsloss is 10%-25% given the procedures currently used in the art (e.g.,the compound loss is 16%, see example 1 in the '778 patent).

The present invention provides a near quantitative utilization of thepharmaceutically active drugs of interest while minimizing thepurification process, e.g., washing and transferring thepharmaceutically active drugs and pharmaceutical compositions. Thepresent invention does not require the total disolvation of thepharmaceutically active drugs, allows the use of less pure reagents andrequires a shorter loading time. The present invention includes awash-free process that provides a near quantitative utilization of thepharmaceutically active drugs of interest. In addition, treatedpost-loading, the particle size of the pharmaceutically activedrugs/resin complex is reduced with little or no agglomeration of theresin particles during preparation. Table IV illustrates the improveddrug utilization by reduced losses of the pharmaceutical composition.When the present invention is compared to the procedure described in the'778 patent, it is clear that less pharmaceutically active drugs arelost with the present invention.

TABLE IV ′778 Patent Present Invention Active Drug Lost 10%-25%   <2%Phenylpropanolamine Lost   16% — Hydrocodone bitartrate Lost >22% <1.0%Phenylephrine HCl Lost —   1.7%

When the pharmaceutically active drugs/resin complex is exposed to asolution (e.g., aqueous media) the unbound pharmaceutically active drugs(i.e., free compound) may dissolve and migrate into the wetted ionexchange resin or migrate out of the wetted ion exchange resin dependingon the equilibrium established. The final distribution or concentrationof the unbound pharmaceutically active drugs and the boundpharmaceutically active drugs are controlled by an equilibrium reactionsubject to variables well known to the skilled artisan, e.g., compoundto resin affinity, compound to resin ratio, media used, presence ofcompeting species or absence of competing species. In addition, the ratecontrolling membrane adjusts the rate at which a new equilibrium isachieved by controlling the interaction with the solvent; however, itdoes not change the ultimate equilibrium distribution.

For example, the present invention provides a pharmaceutical compositionhaving a pharmacologically active drug absorbed onto an ion exchangeresin particles (e.g., IRP-69) to form a pharmaceutically activedrug-resin complex particle. The pharmacologically active drug (or othercompound) and ion exchange resin are suspended/dissolved in a suitableratio in water and the pharmaceutically active drug is allowed to loadonto the ion exchange resin particles. Optionally, a swelling agent maybe added to the suspension at this time. After a suitable period of time(e.g., several hours) the suspension is filtered and the filter cake(e.g., the fraction containing damp resin complex plus some portion ofunbound compound) and liquid filtrate (e.g., the fraction containing theremaining portion of the compound and perhaps swelling agent) arerecovered separately. The suitable period of time may range from 0.1hours to 24 hours and may be of any increment to provide acceptableloading, e.g., 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 2.0,3.0, 4.0, 5.0, 6.0, 7.0, 8.0, 9.0, 10.0, 11.0, 12.0, 13.0, 14.0, 15.0,16.0, 17.0, 18.0, 19.0, 20.0, 21.0, 22.0, 23.0, 24.0 or a combinationthereof. The filter cake is then dried and the filtrate is then appliedback onto the dried filter cake using fluid bed coating equipment orother suitable apparatus or process known to the skilled artisan. Afterapplication of the filtrate, the prepared complex contains virtually allof the compound and all the treating agents present in the originalsuspension.

The prepared compound/resin complex may then be coated with a ratecontrolling membrane to achieve a chosen release profile. Although aportion of the compound is not ionically bound to the ion exchange resinat time of preparation, when wetted (in dissolution media, in syrup orby ingestion) the free drug is available to dissolve and may be releasedor continue to load onto the ion exchange resin depending upon mediaused and formulation ratios.

The '778 patent, and other procedures in which free pharmaceuticallyactive drugs are removed, allow a portion of the bound pharmaceuticallyactive drug to equilibrate quickly into the dissolution media uponhydration. This equilibration allows a modest burst effect that isattenuated by the coating. In the present invention, a portion of theunbound drug equilibrates into the dissolution exhibiting a similarprofile that is modulated by the coating. The extent of this bursteffect may be controlled by manipulation of formulation parameters. Forexample, the present invention provides a modified release profile asillustrated in Table V below. Table V provides the data for the releaseprofile for Phenylephrine Hydrochloride from the drug-resin complex witha 25% coating and FIG. 1 is a graph of the release profile ofPhenylephrine Hydrochloride from the drug-resin complex with a 25%coating.

TABLE V Time % Released 0.5 hr 25.5% 1.0 hr 30.5% 3.0 hr 61.0% 6.0 hr93.0% 12.0 hr  97.0%

Table VI provides the data for the release profile for ahydrocodone-resin complex prepared by the present invention and FIG. 2is a graph of the release profile for hydrocodone/resin prepared by thepresent invention.

TABLE VI Time Sample A 0.5 hr 38.6% 1.0 hr 44.4% 3.0 hr 66.0% 6.0 hr80.4%

In addition, the present invention provides a method of making adrug-resin compound by loading in a solution one or more drugs onto oneor more ion exchange resin particles to form a drug-loaded resinparticle. The drug-loaded resin particle is separated from the solutionand dried. The solution is recombined with the drug-loaded resin to addmore drugs onto the drug-loaded resin particle. The drug-loaded resinparticle is dried after recombining the drug-loaded resin particle withthe solution.

The separating may be accomplished by filtration, extraction,distillation, precipitation, amalgamation or a combination or seriesthereof. The separation may involve one or a series of separationprocedures and may be similar or different in type or in reagents orcomponents used. Solvents may include the solvents known to the skilledartisan, e.g., a non-limiting example includes hexane, benzene, toluene,diethyl ether, chloroform, ethyl acetate, dichloromethane, 1,4-dioxane,tetrahydrofuran, acetone, acetonitrile, dimethylformamide, dimethylsulfoxide, acetic acid, n-butanol, isopropanol, n-propanol, ethanol,methanol, formic acid, water, and mixtures or combinations thereof. Thesolvent may also be in-part or a mixture of alkanes (C5-C8), benzene,benzenethiol, carbon tetrachloride, chlorobenzene, chloroform,cyclohexanethiol, 2-diethylaminoethanol, ethylene dichloride(1,2-dichloroethane), ethyl ether, ethylene glycol monobutyl ether,ethylene glycol monobutyl acetate, ethylene glycol monoethyl ether,ethylene glycol monoethyl ether acetate, ethylene glycol monomethylether, ethylene glycol monomethyl ether acetate, glycidyl ethers,isopropyl alcohol, ketones, methyl alcohol, methylene chloride, phenol,propylene glycol ethers and their acetates, 1,1,2,2-tetrachloroethane,thiols, n-alkane mono, toluene, 1,1,1-trichloroethane,trichloroethylene, xylene, chloroethanes, chloroform, ethylenedibromide, ethylene dibromide, ethylene dichloride (1,2-dichloroethane)glycol ethers: 2-methoxyethanol, 2-ethoxyethanol, hexamethylphosphorictriamide, methylene chloride, halomethanes: methyl chloride, methylbromide, methyl iodide, 2-nitropropane, tetrachloroethylene(perchloroethylene), or trichloroethylene.

The loading step generally includes loading one or more drugs in asolution onto one or more ion exchange resin particles to form adrug-loaded resin particle. The solution may be formed in a variety ofmethods known to the skilled artisan, e.g., the one or more drugs may bein a solution; the one or more ion exchange resin particles may be insolution; both the one or more ion exchange resin particles and the oneor more drugs may be in a solution; neither the one or more ion exchangeresin particles, nor the one or more ion exchange resin particles may bein a solution; the one or more ion exchange resin particles may be insolution; the one or more ion exchange resin particles may be in asolution and combined with another reagent or solution. The step ofloading may last from between about 0.1 and about 12 hours or longerthan about 12 hours.

Furthermore, the one or more sugar alcohols may also be added to thedrug-loaded resin particle, e.g., mannitol, sorbitol, xylitol, maltitol,lactitol, 1,3-dihydroxypropane, inositol glucose, sucrose and mixturesor combinations thereof.

A second drug may be added to the loaded resin particle selected fromnarcotic analgesics, sympathomimetics, antitussives, analgesicsantiemetics, anticholinergics, muscle relaxants, bronchodilators,antibiotics, antidepressants, antiasthmatics, antineoplastics,antiepileptics, cardiovascular agents, mixtures and combinationsthereof.

Examples of the insecticide, acaricide and nematocide that may be usedwith the present invention include pyrethroid compounds (e.g.,permethrin, cypermethrin, fenvarelate, esfenvarelate, fenpropathrin,biphenthrin, deltamethrin, fluvalinate, flucythrinate, allethrin,d-allethrin, prallethrin, cyphenothrin, phenothrin, resmethrin,tefluthrin, empenthrin, acrinathrin, cyhalothrin, cyfluthrin,etofenprox, halfenprox, silafluofen, tralomethrin, cycloprothrin,esbiothrin, transfluthrin, terallethrin, imiprothrin and1-ethynyl-2-fluoro-2-pentenyl3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropanecarboxylate);organophosphorus compounds (e.g., cyanophos, fenthion, fenitrothion,parathion, methylparathion, pirimiphos-methyl, diazinon, isoxathion,pyridaphenthion, chlorpyrifos, chlorpyrifos-methyl, oxydeprofos,vamidothion, malathion, phenthoate, dimethoate, thiometon, disulfoton,phosalone, phosmet, methidathion, prothiofos, sulprofos, profenofos,azinphosmethyl, pyraclofos, salithion, tetrachlorvinphos, dichlorvos,monocrotophos, naled, dimethylvinphos, propaphos, acephate, metamidofosand ethion; carbamate compounds such as carbaryl, metolcarb, isoprocarb,fenobcarb, propoxur, XMC, ethiofencarb, bendiocarb, pyrimicarb,carbosulfan, carbofuran, benfuracarb, furathiocarb, methomyl,thiodicarb, oxamyl, alanycarb, metoxadiazone and fenothiocarb);neonicotinoids (e.g., nitroiminoimidazolidine derivatives,nitrovinylidenediamine derivatives [e.g.N-[(6-chloro-3-pyridylmethyl)-N-ethyl-N′-methyl-2-nitrovinylidenediamine(common name: nitenpyram)], nitroguanidine derivatives, cyanoacetamidinederivatives,N1-[(6-chloro-3-pyridyl)methyl]-N2-cyano-N1-methylacetamidine,cyanoiminothiazolidine derivatives,1-(2-chloro-5-pyridylmethyl)-2-cyanoiminothiazolidine,nitroiminotetrahydro-1,3,5-oxadiazine derivatives,3-[(2-chloro-5-thiazolyl)methyl]-5-methyl-4-nitroiminotetrahydro-1,3,5-oxadiazine(common name: thiamethoxam), nitroiminohexahydro-1,3,5-triazinederivatives,3,5-dimethyl-1-[(2-chloro-5-thiazolyl)methyl]-2-nitroiminohexahydro-1,3,5-triazine;nereistoxin derivatives (e.g., cartap, bensultap and thiocyclam);chlorinated hydrocarbon compounds (e.g., benzoepin, dicofol andtetradifon; formamidine derivatives (e.g., amitraz and chlordimeform);phenylpyrazole derivatives (e.g., ethiprole); benzoylphenylureacompounds (e.g., diflubenzuron, teflubenzuron, chlorfluazuron,flufenoxuron, triflumuron, hexaflumuron, lufenuron and novaluron);triazine derivatives (e.g., cyromazine); thiadiazine derivatives (e.g.,buprofezine); juvenoid compounds (e.g., methoprene, hydroprene,fenoxycarb and diofenolan); tebufenozide; methoxyfenozide; halofenozide;chromafenozide; chlorofenapir; phenisobromolate; quinomethionate;propargit; fenbutatin oxide; hexythiazox; etoxazole; clofentezine;fenpyroximate; tebufenpyrad; pyrimidifen; polynactin complex;milbemectin; avermectin; ivermectin and azadirachtin.

Specific examples of insecticides include:2,3,5,6-tetrafluorobenzyl-chrysanthemate;2,3,5,6-tetrafluorobenzyl-2,2-dimethyl-3-(1-propenyl)cyclopropanecarboxylate; 4-methyl-2,3,5,6-tetrafluorobenzyl-chrysanthemate;4-methyl-2,3,5,6-tetrafluorobenzyl-2,2-dimethyl-3-(2,2-dichlorovinyl)cyclopropanecarboxylate;4-methyl-2,3,5,6-tetrafluorobenzyl-2,2-dimethyl-3-(2,2-difluorovinyl)cyclopropanecarboxylate; 4-methoxymethyl-2,3,5,6-tetrafluorobenzyl-chrysanthemate;4-methoxymethyl-2,3,5,6-tetrafluorobenzyl-2,2-dimethyl-3-(1-propenyl)cyclopropanecarboxylate;2,3,4,5,6-pentafluorobenzyl-2,2-dimethyl-3-(2-chloro-2-trifluoromethylvinyl)cyclopropanecarboxylate; and4-propargyl-2,3,5,6-tetrafluorobenzyl-3-(1-propenyl)-2,2-dimethylcyclopropanecarboxylate. Further, as examples of compounds other than thoseexpressed by formula (I), the following chemicals may be given:4-methoxymethyl-2,3,5,6-tetrafluorobenzyl-2,2,3,3-tetramethylcyclopropanecarboxylate; and4-propargyl-2,3,5,6-tetrafluorobenzyl-2,2,3,3-tetramethylcyclopropanecarboxylate.

Suitable herbicides include: anilides (e.g., diflufenican and propanil),arylcarboxylic acids (e.g., dichloropicolinic acid, dicamba andpicloram), aryloxyalkanoic acids (e.g., 2,4-D, 2,4-DB, 2,4-DP,fluroxypyr, MCPA, MCPP and triclopyr), aryloxy-phenoxy-alkanoic esters(e.g., diclofop-methyl, fenoxaprop-ethyl, fluazifop-butyl,haloxyfop-methyl and quizalofop-ethyl), azinones (e.g., chloridazon andnorflurazon), carbamates (e.g., chlorpropham, desmedipham, phenmediphamand propham), chloroacetanilides (e.g., alachlor, acetochlor, butachlor,metazachlor, metolachlor, pretilachlor and propachlor), dinitroanilines(e.g., oryzalin, pendimethalin and trifluralin), diphenyl ethers (e.g.,acifluorfen, bifenox, fluoroglycofen, fomesafen, halosafen, lactofen andoxyfluorfen), ureas (e.g., chlortoluron, diuron, fluometuron,isoproturon, linuron and methabenzthiazuron), hydroxylamines (e.g.,alloxydim, clethodim, cycloxydim, sethoxydim and tralkoxydim),imidazolinones (e.g., imazethapyr, imazamethabenz, imazapyr andimazaquin), nitriles (e.g., bromoxynil, dichlobenil and ioxynil),oxyacetamides (e.g., mefenacet), sulphonylureas (e.g., amidosulfuron,bensulfuron-methyl, chlorimuron-ethyl, chlorsulfuron, cinosulfuron,metsulfuron-methyl, nicosulfuron, primisulfuron, pyrazosulfuron-ethyl,thifensulfuron-methyl, triasulfuron and tribenuron-methyl),thiocarbamates (e.g., butylate, cycloate, di-allate, EPTC, esprocarb,molinate, prosulfocarb, thiobencarb and tri-allate), triazines (e.g.,atrazine, cyanazine, simazine, simetryne, terbutryne and terbutylazine),triazinones (e.g., hexazinone, metamitron and metribuzin), others (e.g.,aminotriazole, benfuresate, bentazone, cinmethylin, clomazone,clopyralid, difenzoquat, dithiopyr, ethofumesate, fluorochloridone,glufosinate, glyphosate, isoxaben, pyridate, quinchlorac, quinmerac,sulphosate and tridiphane).

It is contemplated that any embodiment discussed in this specificationcan be implemented with respect to any method, kit, reagent, orcomposition of the invention, and vice versa. Furthermore, compositionsof the invention can be used to achieve methods of the invention.

It will be understood that particular embodiments described herein areshown by way of illustration and not as limitations of the invention.The principal features of this invention can be employed in variousembodiments without departing from the scope of the invention. Thoseskilled in the art will recognize, or be able to ascertain using no morethan routine experimentation, numerous equivalents to the specificprocedures described herein. Such equivalents are considered to bewithin the scope of this invention and are covered by the claims.

All publications and patent applications mentioned in the specificationare indicative of the level of skill of those skilled in the art towhich this invention pertains. All publications and patent applicationsare herein incorporated by reference to the same extent as if eachindividual publication or patent application was specifically andindividually indicated to be incorporated by reference.

The use of the word “a” or “an” when used in conjunction with the term“comprising” in the claims and/or the specification may mean “one,” butit is also consistent with the meaning of “one or more,” “at least one,”and “one or more than one.” The use of the term “or” in the claims isused to mean “and/or” unless explicitly indicated to refer toalternatives only or the alternatives are mutually exclusive, althoughthe disclosure supports a definition that refers to only alternativesand “and/or.” Throughout this application, the term “about” is used toindicate that a value includes the inherent variation of error for thedevice, the method being employed to determine the value, or thevariation that exists among the study subjects.

As used in this specification and claim(s), the words “comprising” (andany form of comprising, such as “comprise” and “comprises”), “having”(and any form of having, such as “have” and “has”), “including” (and anyform of including, such as “includes” and “include”) or “containing”(and any form of containing, such as “contains” and “contain”) areinclusive or open-ended and do not exclude additional, unrecitedelements or method steps.

The term “or combinations thereof” as used herein refers to allpermutations and combinations of the listed items preceding the term.For example, “A, B, C, or combinations thereof” is intended to includeat least one of: A, B, C, AB, AC, BC, or ABC, and if order is importantin a particular context, also BA, CA, CB, CBA, BCA, ACB, BAC, or CAB.Continuing with this example, expressly included are combinations thatcontain repeats of one or more item or term, such as BB, AAA, MB, BBC,AAABCCCC, CBBAAA, CABABB, and so forth. The skilled artisan willunderstand that typically there is no limit on the number of items orterms in any combination, unless otherwise apparent from the context.

All of the compositions and/or methods disclosed and claimed herein canbe made and executed without undue experimentation in light of thepresent disclosure. While the compositions and methods of this inventionhave been described in terms of preferred embodiments, it will beapparent to those of skill in the art that variations may be applied tothe compositions and/or methods and in the steps or in the sequence ofsteps of the method described herein without departing from the concept,spirit and scope of the invention. All such similar substitutes andmodifications apparent to those skilled in the art are deemed to bewithin the spirit, scope and concept of the invention as defined by theappended claims.

1-24. (canceled)
 25. A product obtained by: loading in a solution one ormore drugs onto one or more ion exchange resin particles to formdrug-loaded resin particle(s); separating the drug-loaded resinparticle(s) from the solution and recovering a filtrate containingunbound drug; and coating the recovered filtrate back onto thedrug-loaded resin particle(s).
 26. The product of claim 25, furthercomprising the step of drying the drug-loaded resin particle(s) thencoating the recovered filtrate back onto the drug-loaded resin particle.27. The product of claim 25, wherein the step of separating is selectedfrom the group consisting of filtration, extraction, distillation,precipitation, amalgamation or a combination or series thereof.
 28. Theproduct of claim 25, wherein the drying is accomplished by the use of anoven dryer, flash dryer, spray dryer, a fluid bed dryer or a combinationthereof.
 29. The product of claim 25, wherein the step of loading lastsbetween about 0.1 and 12 hours.
 30. The product of claim 25, furthercomprising the step of loading one or more sugar alcohols to thedrug-loaded resin particle(s).
 31. The product of claim 30, wherein theone or more sugar alcohols is selected from the group consisting ofmannitol, sorbitol, xylitol, maltitol, lactitol, 1,3-dihydroxypropane,inositol glucose, sucrose and mixtures or combinations thereof.
 32. Theproduct of claim 25, wherein the ion exchange resin particles comprisesulfonic acid cationic exchange resin particles.
 33. The product ofclaim 25, wherein the ionic exchange resin is selected from the groupconsisting of dipropylene glycol diallyl ether, polyglycol diallylether, triethylene glycol divinyl ether, hydroquinone diallyl ether,tetraallyloxyethanoyl, vinyl ether, vinyl acetate, vinyl butylbenzoate,crotonic acid, polyfunctional alcohol, tetraethylene glycol diacrylate,triallylamine, trimethylolpropane diallyl ether, methylenebisacrylamide,divinylbenzene, phthalic, sulphonphthalic acid, ethylene glycol,polymethyl siloxane α,γ-hydroxypropyl or combination thereof.
 34. Theproduct of claim 25, wherein the loading solution comprises a seconddrug selected from narcotic analgesics, sympathomimetics, antitussives,analgesics antiemetics, anticholinergics, muscle relaxants,bronchodilators, antibiotics, antidepressants, antiasthmatics,antineoplastics, antiepileptics, cardiovascular agents, mixtures andcombinations thereof.
 35. The product of claim 25, further comprisingthe step of coating the ion exchange resin particles with awater-permeable diffusion barrier.
 36. The product of claim 25, furthercomprising the step of drying the drug-loaded resin particle(s) afterthe separation of the drug-loaded resin particle(s) from the solution.37. The product of claim 25, wherein the recovered filtrate is coatedback onto the drug-loaded resin particle(s) using a fluid bed coatingequipment.
 38. The product of claim 25, wherein the one or more drugs isselected from the group consisting of narcotic analgesics,sympathomimetics, antitussives, analgesics antiemetics,anticholinergics, muscle relaxants, bronchodilators, antibiotics,antidepressants, antiasthmatics, antineoplastics, antiepileptics,cardiovascular agents, mixtures and combinations thereof.
 39. Theproduct of claim 25, wherein the one or more drugs is selected from thegroup consisting of codeine, dihydrocodeine, hydromorphone, morphine,pentazocine, propoxyphene, norephedrine, pseudoephedrine,dextromethorphan, aspirin, tramadol, metoclopramide, atropine,ipratropium bromide, scopolamine, cyclobenzaprine, papaverine,salbutamol, terbutaline and theophylline, amoxycillin, ampicillin,azlocillin, bacampicillin, cefamandole, cefonicid, cefotaxime,cefotetan, cefoxitin, ceftriaxone, mezlocillin, piperacillin, bupropion,nomifensine, nortriptyline, cromolyn, tamoxifen, valproic acid andphenvtoin, propranolol mixtures and combinations thereof.
 40. Theproduct of claim 35, further comprising suspending the drug-loaded resinparticle(s) in a liquid.
 41. The product of claim 40, wherein the liquidis a syrup.
 42. The product of claim 25, wherein the drug-resin compoundis a controlled release composition.
 43. The product of claim 41 whereinthe drug is dextromethorphan or a pharmaceutically acceptable saltthereof.
 44. The product of claim 41 wherein the drug is codeine or apharmaceutically acceptable salt thereof.
 45. The product of claim 41wherein the drug is hydrocodone or a pharmaceutically acceptable saltthereof.